
==== Front
Biomed J
Biomed J
Biomedical Journal
2319-4170
2320-2890
Chang Gung University

S2319-4170(24)00052-0
10.1016/j.bj.2024.100749
100749
VSI: Extracellular Vesicles and Exosomes
Intercellular transfer of MHC molecules in T cell alloimmunity and allotransplantation
Benichou Gilles gbenichou@mgh.harvard.edu
⁎
Lancia Hyshem H.
Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, MA, USA
⁎ Corresponding author. Department of Surgery, Massachusetts General Hospital, Thier 807, 55 Fruit Street, Boston, MA, 02114, USA. gbenichou@mgh.harvard.edu
25 5 2024
10 2024
25 5 2024
47 5 10074923 12 2023
15 5 2024
24 5 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
After transplantation of allogeneic tissues and organs, recognition by recipient T cells of donor MHC molecules initiates the pro-inflammatory adaptive immune response leading to allograft rejection. T cell allorecognition has long been known to be mediated via two distinct pathways: the direct pathway in which T cells recognize intact allogeneic MHC molecules displayed on donor cells and the indirect pathway whereby T cells recognize donor MHC peptides processed and presented by recipient antigen-presenting cells (APCs). It is believed that direct allorecognition is the driving force behind early acute allograft rejection while indirect allorecognition is involved in chronic allograft rejection, a progressive condition characterized by graft vasculopathy and tissue fibrosis. Recently, we and others have reported that after transplantation of allogeneic skin and organs, donor MHC molecules are transferred from donor cells to the host's APCs via trogocytosis or extracellular vesicles. Recipient APCs having captured donor MHC molecules can either present them to T cells in their intact form on their surface (semi-direct pathway) or the form of peptides bound to self-MHC molecules (indirect pathway). The present article provides an overview of recent studies evaluating the role of intercellular exchange of MHC molecules in T cell alloimmunity and its contribution to allograft rejection and tolerance.

Highlights

• This article provides an overview of the role of intercellular exchange of major histocompatibility complex molecules in T cell allorecognition involved in rejection and tolerance of allografts.
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pmc1 Introduction

Allorecognition is a process by which an individual organism can distinguish between its own cells and those of another individual from the same species. In vertebrates, T lymphocytes activated through recognition of allogeneic MHC molecules initiate and orchestrate the adaptive immune response leading to allograft rejection. On the other hand, under certain circumstances, recognition of allogeneic MHC molecules by T cells can lead to the deletion of alloreactive T cells or donor-specific regulatory immunity associated with tolerance of alloantigens and long-term survival of allografts.

Two distinct mechanisms are traditionally involved in T cell allorecognition: the direct pathway in which T cells recognize intact allogeneic MHC proteins displayed on the surface of donor antigen-presenting cells (APCs) and the indirect pathway in which T cells recognize donor MHC peptides processed and presented by self-MHC molecules on recipient APCs [Fig. 1]. Direct and indirect activation of T cells are believed to occur in the recipient's secondary lymphoid organs through recognition of MHC molecules carried by donor MHC class II+ leukocytes having migrated from the graft through lymphatic vessels (passenger leukocytes). Direct allorecognition triggers a polyclonal inflammatory response engaging 1–10 % of the T cell repertoire [[1], [2], [3], [4], [5], [6], [7], [8], [9]]. Two mechanisms account for the high frequency of T cells being activated through this pathway: the high determinant density and the multiple binary complex models [[9], [10], [11]]. The first model postulates that the alloreactive T cells recognize essentially allogeneic MHC molecules themselves independently of the peptides bound to them. Consequently, every single foreign MHC molecule displayed on an allogeneic APC could serve as a ligand for alloreactive T cells, thereby creating a high determinant density. The second model proposes that alloreactive T cells recognize defined allogeneic MHC-peptide complexes. Since MHC molecules are bound to a wide variety of peptides, a single allogeneic MHC molecule could stimulate many alloreactive T cell clones, each specific for a single MHC-peptide complex. In contrast to direct allorecognition, indirect alloresponses by T cells are oligoclonal and directed toward a selected set of dominant peptides derived from allogeneic MHC molecules and minor histocompatibility antigens [12,13]. While direct alloresponses by T cells are traditionally considered the driving force behind acute allograft rejection, there is circumstantial evidence suggesting that indirect T cell alloimmunity is involved in chronic rejection, a progressive condition characterized by obstruction of graft blood vessels and tissue fibrosis [[14], [15], [16], [17], [18], [19], [20], [21]].Fig. 1 Allorecognition by T cells is mediated via three distinct pathways. In the direct pathway, T cells recognize allogeneic MHC molecules displayed on the membrane of donor APCs. In the indirect pathway, T cells interact with allogeneic peptides (MHC and mHA) processed and presented by recipient APCs. In the semi-direct pathway, T cells recognize allogeneic MHC molecules transferred to and presented by recipient APCs.

Fig. 1

Recently, several studies have documented the existence of a third mechanism of T cell allorecognition called the semi-direct pathway [Fig. 1]. it was observed that after skin and solid organ transplantation, allogeneic MHC molecules are regularly transferred from donor to recipient APCs [[22], [23], [24], [25], [26]]. Consequently, recipient APCs having acquired donor MHC molecules display intact allogeneic MHC antigens on their surface (donor MHC cross-dressing) and thereby activate allospecific T cells [Fig. 1]. In addition, intercellular transfer of MHC proteins can result in their processing into peptides by recipient APCs and subsequent indirect presentation to T cells. Some of these studies have shown the role of extracellular vesicles in the inter-cellular transfer of MHC molecules between donor and recipient APCs in different transplant models. While there is accumulating evidence that intercellular transfer of MHC molecules plays a key role in allograft rejection, a few studies suggest that this phenomenon is also involved in transplant tolerance. The present article provides an overview of current knowledge regarding the contribution of intercellular transfer of MHC molecules in T cell alloresponses leading to allograft rejection or tolerance. The implications of these findings for the development of novel therapies in transplantation are discussed.

2 Intercellular transfer of MHC molecules in immunity

Molecules such as proteins and nucleic acids such as mRNA and miRNA are regularly exchanged between cells of the immune system [27]. Such intercellular molecular transfer occurs via cell-cell contact or vesicles or through transport via nanotubes [27]. Forty years ago, T cells were shown to acquire surface immunoglobulin molecules from B cells [28] and antigens from macrophages [29]. Likewise, a variety of molecules such as MHC-peptide complexes, Immunoglobulins, costimulation, adhesion, and extracellular matrix organization molecules as well as viral, chemokine, and complement receptors are regularly exchanged between dendritic cells, monocytes, endothelial cells as well as NK cells and T and B lymphocytes [30]. There is now plenty of evidence showing that intercellular transfer of molecules between leukocytes plays a key role in the initiation and regulation of immunity in health and disease [27,30,31].

The transfer of MHC molecules between hematopoietic cells was initially documented by Frelinger et al., in 1974 [32]. This study showed the acquisition of MHC class II molecules by mouse T lymphocytes, which were normally devoid of these molecules [32]. This observation was then confirmed and extended to other leukocytes by R. Lechler and others [[33], [34], [35]]. The passage of intact MHC molecules loaded with antigen peptides was subsequently coined as MHC cross-dressing by Yewdell and Haeryfar [36]. It is now well documented that both MHC class I and II-peptide MHC complexes are regularly transferred from APCs to other APCs as well as APCs to T and B cells and between lymphocytes [30]. MHC molecules can be transferred via cell-cell contact through nibbling also called trogocytosis (named after the Greek word trogo (to nibble)) [34,37,38] or via trans-synaptic transfer i.e. through receptor-ligand interaction [39]. In addition, MHC cross-dressing can be mediated via binding to extracellular vesicles released by leukocytes, including exosomes [[40], [41], [42]]. Intercellular transfer of MHC-peptide complexes is involved in several physiological immune processes including the initiation of T cell responses in secondary lymphoid organs [30]. For instance, dermal DCs having processed antigens migrate to regional lymph nodes and transfer MHC-peptide complexes to lymphoid-resident DCs for presentation to cytotoxic T cells [43]. Such MHC-peptide antigen transfer between DCs is considered to amplify presentation across a larger network of lymphoid-resident DCs thus maximizing T cell activation [43]. Intercellular transfer of MHC-peptide complexes is also believed to play a key role in T cell differentiation and repertoire selection in the developing thymus. Millet et al. showed polarized, and cell-cell contact-dependent transfer of MHC class II-peptide complexes from medullary thymic epithelial cells (mTECs) to dendritic cells occurring in vivo using bone marrow and somatic chimeras [44]. In another study, exosomal transfer of self-peptide-MHC complexes from mTECs to thymic DCs has been described as a mechanism allowing DCs to acquire tissue-restricted antigens thus contributing to negative selection and regulatory T cell generation [45,46]. In addition, the acquisition of MHC-peptide complexes by APCs is known to participate in the immune response to microbes and cancer cells [31]. Indeed, the transfer of MHC class I molecules loaded with microbial and tumor antigen peptides to professional APCs and subsequent activation of CD8+ T cells plays a key role in anti-microbial and anti-tumor immunity [47,48]. In addition, efficient vaccination against tumor cells in mice has been shown to rely on CD4+ T cell responses elicited via antigen presentation by host DCs cross-dressed with peptide-MHC complexes acquired from the injected cells [49,50]. Therefore, intercellular exchange of MHC class I and II molecules between leukocytes plays an essential role in all aspects of adaptive immunity. The next chapters provide a detailed overview of the role of this phenomenon in alloimmune responses by T cells, which is the focus of this article.

3 Intercellular transfer of MHC molecules in T cell alloreactivity and allograft rejection

3.1 APCs cross-dressed with donor MHC molecules can activate alloreactive T cells

In 1999, a study by Bedford and colleagues provided some evidence suggesting that mixed lymphocyte reactions (MLR) could be mediated through the transfer of allogeneic MHC class II molecules between DCs [51]. One year later, Russo and colleagues showed in vitro acquisition of intact allogeneic HLA molecules by DCs [52]. In this study, transfer of MHC class I and II molecules from melanoma cells to DCs observed in co-cultures required cell-cell contact and involved transfer of lipids. In this setting, the half-life of transferred molecules was 10–20 h, which is similar to that measured with endogenous self-MHC class I proteins. Of note, this process was uni-directional as no molecular transfer was observed from DCs to melanoma cells. Most importantly, DCs having acquired an allogeneic HLA-A2 MHC class I antigen were recognized and killed by allospecific cytotoxic T cells [52]. Subsequently, reports from Lechler's laboratory demonstrated that mouse and human APCs cross-dressed with allogeneic MHC molecules could trigger the proliferation of alloreactive T cells in vitro [34,53]. This phenomenon was referred to as semi-direct pathway of allorecognition. In these studies, involving cell co-cultures, MHC transfer between DCs or endothelial cells (ECs) required cell-cell contact in a temperature- and energy-dependent manner [34,53]. Moreover, it was observed that B10.A(4R) mouse DCs lacking MHC class II H-2Ek expression, which had acquired allogeneic MHC class II molecules following in vivo adoptive transfer in B10.A(2R) mice (H-2Ek+) could stimulate in vitro T cell clones specific for H2-Ek-peptide complexes [34,53]. In this model, it was plausible that injected DCs had acquired H-2Ek expression from host ECs upon their trafficking into lymphoid organs. If occurring after transplantation, one can speculate that such MHC class II transfer between donor ECs and recipient DCs may be a central mechanism in the initiation or perpetuation of the CD4+ T cell alloresponse within the allograft (after elimination of donor leukocytes).

3.2 Contribution of intercellular transfer of MHC molecules to T cell alloreactivity in transplanted mice

In 2008, a study from W. Wong's laboratory showed bidirectional transfer of MHC class II molecules between donor and recipient cells in mice transplanted with a heart or kidney allograft [22]. MHC-cross-dressed cells detected in the host's spleen were comprised primarily of DCs and a few B cells and macrophages. Likewise, in 2014, a paper by Markey et al. documented extensive cross-dressing of donor cells with recipient MHC class I and II molecules following allogeneic bone marrow transplantation in mice [54]. This process was found to maximize CD4+ T cell responses to indirectly presented antigens [54]. One year later, Harper and colleagues provided strong circumstantial evidence supporting the functional relevance of semi-direct allorecognition by T cells in acute rejection of cardiac allografts in mice [55]. In this study, it was observed that recipient DCs can acquire donor MHC class I proteins from the graft and present it both as intact protein to CD8+ T cells and as processed peptides to CD4+ T cells [55]. The potential relevance of such simultaneous semi-direct and indirect presentation of donor MHC antigens by recipient APCs in allograft rejection is discussed later in this review. In 2016, one publication from our group at MGH and an article from Morelli's laboratory at U. Pittsburgh revealed the central role of extracellular vesicles in donor MHC cross-dressing and semi-direct alloresponses by T cells induced after transplantation [23,24]. In our study, we first revisited the so-called passenger leukocyte theory in skin-grafted mice [23]. To detect the presence of donor leukocytes in the recipient's lymph nodes and spleen, we used a technique of imaging flow cytometry (Amnis), which combines flow cytometry and microscopy. To our surprise, we found no donor leukocytes in secondary lymphoid organs of mice transplanted with an allogeneic skin patch at any time point post-transplantation (day 2–10) [23]. This result was confirmed through PCR analyses [23]. This correlated with a previous report by Celli et al. using two-photon microscopy showing that donor dermal DCs were rapidly eliminated (presumably by NK cells) after ear skin transplantation [56]. Actually, in the latter study, while a few donor DCs were transiently detected in the graft-draining lymph nodes, they lacked membrane dynamics and had the appearance of dead cells or cell debris [56]. While our study failed to detect donor cells in the recipient's lymph nodes of skin-grafted mice, imaging flow cytometry revealed the presence of recipient cells bound to vesicles displaying donor MHC class I and II molecules as early as day 2 post-transplantation [23]. By day 7 post-skin grafting, the vesicles were no longer visible and the cells were double-positive i.e. they expressed both recipient and donor MHC molecules on their surface [23]. In mice transplanted with an allogeneic heart, a small number (100 cells per spleen) of donor leukocytes were actually detected in the recipient's spleen [23]. This observation confirmed seminal findings by C. Larsen showing the presence of MHC class II+ passenger leukocytes in the spleen of heart-transplanted mice [57]. It is likely that, unlike skin grafts, primary vascularization of these transplants is associated with reverse transmigration of some donor leukocytes. However, these few donor leukocytes became rapidly undetectable due presumably to their elimination by the host's immune system, as previously reported [58]. In contrast, high frequencies of recipient cells cross-dressed with donor MHC antigens (>50,000 cells) were found in the spleen of mice transplanted with an allogeneic heart [23]. Although the precise nature of donor EVs mediating cross-dressing was not established in our study, their high expression of MHC class II molecules suggested that they corresponded to exosomes derived from multivesicular bodies (MVBs) formed in the endosomal compartment. The study published by Liu et al. the same year confirmed these observations and provided some key additional insights into this phenomenon [24]. Similar to our observations, Liu and colleagues detected very few donor cells (400 cells/spleen at day 3 post-transplantation) but high numbers of recipient cells cross-dressed with donor MHC molecules (>50,000 cells) in the spleen of heart-transplanted mice [24]. Efficient expression of donor MHC molecules on recipient conventional DCs (cDCs) depended on the transfer of EVs from donor DCs that had migrated from the graft to lymphoid tissues [24]. These EVs were present in the form of clusters and exhibited characteristic features of exosomes based on their diameters (70–120 nm) and tetraspanin expression (CD9 and CD63). The nature of EVs was further supported by experiments showing that intercellular transfer of MHC molecules between DCs was abrogated in vitro by an inhibitor of exosome formation, Rab27a siRNA, but not imipramine and DEVD, which impaired the release of microvesicles (ectosomes) and apoptotic vesicles, respectively [24]. Apparently, donor exosomes did not fuse with the plasma membrane but were internalized or remained attached to the recipient cDCs [24]. Most importantly, recipient cDCs that had acquired donor exosomes in transplanted mice were shown to be activated and to stimulate alloreactive T cells [24]. In a subsequent study, L. Smyth documented that continuous acquisition of donor MHC class I-peptide complexes was essential to the generation of allospecific CD8+ T cell-mediated immunity after skin transplantation [59]. In addition, the results showed that MHC transfer lasted for the life of the transplant and was dependent on inflammation of the graft [59]. In this study, significant numbers of donor leukocytes were detected in the lymph nodes of skin-grafted mice for up to 14 days. This apparent discrepancy with our report may be because this study involved poorly immunogenic minor antigen-mismatched allografts (OVA) while ours was performed with fully MHC disparate skin grafts. Finally, a more recent study from the Lakkis' laboratory investigated the presence of cross-dressed dendritic cells within islet and kidney allografts [26]. Using imaging cytometry and multi-photon intravital microscopy, they observed extensive cross-dressing of intragraft host DCs with donor MHC-peptide complexes that took place early after transplantation, whereas host DCs presenting donor antigen in an indirect fashion were scarce [26]. Cross-dressed DCs stably engaged TCR-transgenic effector CD8+ T cells specific for alloantigens and were sufficient for sustaining acute allograft rejection [26].

Taken together, the aforementioned studies showed that intercellular exchange of MHC class I and II molecules between DCs and other leukocytes as well as endothelial cells and presumably parenchymal cells occurs regularly after skin, islet, bone marrow and solid organ transplantation. This phenomenon occurs via cell-cell contact or through EVs, including exosomes. APCs having acquired allogeneic MHC molecules can either display them in intact form on their surface (semi-direct presentation) or as processed peptides in association with self-MHC molecules (indirect presentation). Furthermore, there is now ample evidence showing that after transplantation, recipient APCs cross-dressed with allogeneic MHC antigens activate pro-inflammatory alloreactive CD4+ and CD8+ T cells in the recipient's secondary lymphoid organs and most probably within the transplant itself.

3.3 Contribution of semi-direct allorecognition to allograft rejection

Since recipient APCs having acquired allogeneic MHC molecules can activate alloreactive T cells in vitro and in vivo, one can speculate how and to which extent this phenomenon contributes to the rejection of an allograft. It is likely that donor passenger leukocytes are rapidly eliminated by the host's immune system while high numbers of recipient professional APCs are detected in the secondary lymphoid organs of transplanted mice [56,58]. This suggests that the presentation of intact donor MHC antigens on cross-dressed cells rather than donor leukocytes drives the early alloimmune response by T cells leading to acute allograft rejection. This view is supported by results from the Pettigrew's laboratory showing that CD8+ cytotoxic T cell-mediated rejection of heart allografts lacking bone marrow-derived APCs requires host secondary lymphoid organs [55]. Therefore, semi-direct alloantigen presentation by recipient APCs rather than direct presentation by donor APCs may be the driving force behind polyclonal activation of pro-inflammatory alloreactive T cells against intact donor MHC molecules initiating early acute allograft rejection. In addition, it is likely that allogeneic MHC molecules transferred to recipient APCs via donor vesicles or cell-cell contact represent a major source of antigen for peptide processing and presentation through indirect allorecognition. In support of this view, Morelli and colleagues have documented that proteins contained in exosomes endocytosed by DCs are processed in the endocytic compartment and presented as allopeptides to CD4+ T cells i.e. through the indirect allorecognition pathway [40]. Based upon these principles, it is conceivable that recipient APCs could present simultaneously donor MHC or minor histocompatibility antigen (mHAs) peptides bound to self-MHC class II molecules (indirect presentation) as well as intact donor MHC class I on their surface (semi-direct presentation) (three-cell model) [Fig. 2]. This type of presentation could explain how indirectly activated CD4+ T cells can provide optimal help for the activation and differentiation of CD8+ cytotoxic T cells. This model would comply with the dogma that CD4+ and CD8+ T cells need to recognize peptide-MHC complexes on the same APC and provide a plausible explanation for the four-cell model conundrum of direct and indirect allorecognition by T cells in transplantation [Fig. 2]. For instance, in corneal transplantation, acute rejection is driven exclusively by CD4+ T cells recognizing mHAs in an indirect fashion [[60], [61], [62], [63], [64]]. Lack of a direct CD4+ T cell response results from the immune-privileged nature of these grafts containing APCs devoid of allogeneic MHC class II expression at the time of transplantation [65]. In this model, it is conceivable that CD8+ T cells become activated via recognition of allogeneic MHC class I acquired by recipient bona fide APCs presenting at the same time self-MHC class II proteins bound to donor mHAs. Finally, presentation of donor MHC molecules displayed on recipient APCs can contribute to B cell alloresponses. Zeng and colleagues have recently shown that exosomes released by cardiac allografts are captured by subcapsular sinus macrophages in recipient lymph nodes. These cross-dressed macrophages present donor MHC molecules to alloreactive B cells thereby inducing the production of donor-specific antibodies (DSA) [66].Fig. 2 Three-cell versus four-cell models of CD4+T cell help for CD8+T cell alloresponse.In the four-cell model, CD4+ T cells and CD8+ T cells recognize recipient MHC class II molecules + donor peptides (indirect pathway) on recipeint APCs and donor MHC class I on donornAPCs (direct pathway), respectively. In the three-cell model, CD4+ T cells recognizing allogeneic peptides bound to recipient MHC class II molecules on recipient APCs (indirect pathway) provide help to alloreactive CD8+ T cells recognizing donor MHC class I molecules acquired by (MHC cross-dressing) and presented on the same recipient APCs (semi-direct pathway).

Fig. 2

Although it is not in accord with the current dogma, the possibility that some T cells may be activated within the allograft and cause rejection has never been formally ruled out. This concept called “peripheral sensitization” in which the donor antigens activate circulating lymphocytes as they traffic through the vascular bed of the transplant was proposed in the 1960s by Medawar and Strober [67,68]. More recently, we and others showed that mice devoid of secondary lymphoid organs rejected skin allografts in an acute fashion [69,70]. The observations reported by the Lakkis' group showing extensive cross-dressing of recipient APCs infiltrating allografts suggest that semi-direct alloreactivity might represent a mechanism for amplifying and perpetuating T cell alloimmunity within the graft [26]. Finally, it is conceivable that intra-graft recipient cells cross-dressed with donor MHC class I antigens, including vascular endothelial cells, could serve as targets for alloreactive cytotoxic CD8+ T cells (CTLs). Subsequent attacks of graft blood vessels displaying donor MHC class I antigens could participate in local inflammation and acute allograft rejection.

Taken together, these studies suggest that intercellular transfer of MHC and minor histocompatibility antigens plays an essential role in allograft rejection. However, experiments designed to suppress donor antigen cross-dressing of recipient cells in vivo and evaluate the effect of such treatment on the alloresponse and graft rejection would be required to validate this point. Up to now, the most compelling evidence of the contribution of EVs and MHC cross-dressing to allograft rejection has been provided by a recent report by Zeng and colleagues [66]. In this study, mice were treated with GW4869, which is a neutral shingomyelinase inhibitor that impairs exosome biogenesis and then transplanted with an allogeneic heart. GW4869 treatment reduced the percentages of recipient APCs cross-dressed with donor MHC class I antigens in secondary lymphoid organs, reduced DSA titers in blood and significantly prolonged allograft survival [66].

The contribution of EVs and antigen cross-dressing in chronic allograft rejection is unknown. Chronic rejection, which is characterized by progressive fibrosis of graft tissue and obstruction of blood vessels (graft vasculopathy) resulting in loss of graft functions, is a major problem in clinical transplantation [[71], [72], [73], [74], [75]]. While there is plenty of evidence showing the role of CD4+ T cells in chronic rejection, the mechanisms by which they contribute to this condition are poorly understood. There is circumstantial evidence suggesting that CD4+ T cells activated via indirect allorecognition play a key role in chronic rejection partly through their ability to provide help to alloreactive B cells secreting alloantibodies [76,77]. In support of this view, elegant studies by Pettigrew's laboratory et al. have demonstrated that indirect pathway responses alone can effect chronic rejection through providing help for chronic humoral alloimmune responses [78]. It is conceivable that once professional donor APCs have been eliminated, continuous transfer of allogeneic MHC molecules on recipient APCs could maintain T cell alloimmunity to both intact donor MHC molecules (semi-direct pathway) and donor peptides presented indirectly. Actually, this view is supported by Hughes' paper showing significant numbers of cross-dressed cells several weeks after transplantation in a kidney chronic rejection mouse model [26]. It is also noteworthy that Dieudé's studies have documented the role of exosome-like vesicles produced by endothelial cells in antibody production and allograft inflammation in mice transplanted with allogeneic aortic grafts [79]. This suggests that endothelial cells could be a major source of EVs for cross-dressing and T cell activation in chronic rejection. Finally, studies from Mohanakumar's laboratory suggest the potential role of donor-derived exosomes in chronic rejection (bronchiolitis obliterans syndrome) of lung allografts [80]. Altogether, these studies suggest that EVs and antigen cross-dressing could be involved in chronic allograft rejection. However, further investigations are needed to validate this concept.

4 Intercellular transfer of MHC molecules in allograft tolerance

Achieving allograft tolerance, which is defined as a lack of destructive immunity resulting in long-term transplant survival in the absence of ongoing immunosuppression, is the ultimate goal in clinical transplantation. Based on numerous studies supporting the role of donor MHC cross-dressing in transplant rejection, it seems counterintuitive to believe that this phenomenon is also involved in tolerance of allografts. However, one should keep in mind that while the presentation of allogeneic MHC molecules is the driving force behind allograft rejection, it is also necessary to achieve transplant tolerance via hematopoietic chimerism or donor-specific transfusion [[81], [82], [83], [84], [85]]. Indeed, tolerogenicity is not an intrinsic property of a given antigen, but it depends on the context in which the antigen is presented to T cells, including the nature of the APCs, their state of differentiation, and their ability to provide costimulatory signals. For instance, antigen presentation in the absence of positive costimulation leads to a state of T cell unresponsiveness called anergy [[86], [87], [88]]. In addition, antigen presentation in the presence of coinhibitory signals given by APCs can lead to the activation of Foxp3 regulatory T cells (Tregs) and other regulatory T cells such as Tr1 or Th3 cells [[89], [90], [91], [92]]. In summary, antigen presentation in the absence of inflammation and danger signals can lead to T cell inactivation or deletion resulting in T cell tolerance. Based on these principles, it is conceivable that, under certain circumstances, graft-derived EVs and recipient APCs cross-dressed with allogeneic MHC proteins could contribute to the induction and/or maintenance of allograft tolerance. For instance, in the absence of inflammation, MHC molecules carried by exosomes produced by allografts either via cross-dressing of APCs or on their own could anergize T cells or cause T cell exhaustion. A recent study from our laboratory showed that allogeneic exosomes could bind to TCR on T cells but, unlike APCs cross-dressed with allogeneic MHC antigens, they did not activate allospecific T cells in vitro [93]. In vivo, allogeneic exosomes could stimulate an alloresponse and accelerate rejection of an allograft but only when administered with complete Freund's adjuvant i.e. in an inflammatory milieu [93]. Based on these results, it could be hypothesized that allogeneic exosomes could be tolerogenic in the absence of inflammation. A report by Pêche et al. actually showed that administration of rats with donor exosomes along with LF 15–0195, an inhibitor of DC maturation achieved tolerance of cardiac allografts in rats [94]. This suggests that antigen presentation by immature recipient DCs cross-dressed with donor MHC antigens had achieved allograft tolerance although the role of intercellular exchange of MHC antigens was not evaluated in this study. The most convincing evidence of the role of MHC cross-dressing in T cell tolerance of alloantigens was provided by a series of articles on fetal-maternal tolerance and liver transplant tolerance [[95], [96], [97]].

Maternal microchimerism acquired during pregnancy and breast-feeding is associated with immune tolerance to non-inherited maternal antigens (NIMA), including MHC antigens, in offspring [[98], [99], [100], [101]]. Tolerance of NIMA has been shown to promote solid organ transplant acceptance in experimental mouse models and kidney-transplanted patients [[98], [99], [100], [101]]. A recent study by Bracamonte et al., showed that maternal microchimerism was associated with NIMA acquisition of DCs via maternal EV-mediated cross-dressing [95,96]. This process resulted in “split” tolerance whereby CD4+ T cells recognizing intact allo-MHC molecules (direct pathway) were stimulated while CD4+ T cells responding to allopeptides in a self-MHC–restricted manner were silenced (indirect pathway) [95]. These results, along with a previous report by Kinder et al. [102] may provide an explanation for the original observations of split tolerance to NIMA-Rh made by Owen et al. [103]. Intercellular transfer of HLA-G MHC class I molecules during pregnancy is another example whereby cross-dressing is involved in immune privilege and fetal-maternal tolerance [104]. During pregnancy, while semi-allogeneic fetal extravillous trophoblasts (EVT) invade the uterine mucosa, they fail to be destroyed by the maternal immune system [104]. This immune privilege property is associated with expression in EVT of a non-classical and poorly polymorphic MHC class I molecule called HLA-G [104]. HLA-G expression results in the inhibition of decidual natural NK (dNK) cell cytotoxic functions [104]. Most importantly, during interactions with EVT, HLA-G molecules have been shown to be transferred to dNK cells via trogocytosis [104]. It is likely that this mechanism has been selected due to the fact that KIRDL4, the main HLA-G receptor expressed by dNK cells is located intracellularly in endosomes and mediates its signal after interacting with HLA-G molecules in endolysosomes [105]. Furthermore, HLA-G molecules are also transferred regularly to CD4+ T cells and thereby confer regulatory functions to these cells [106]. Therefore, intercellular transfer of HLA-G MHC class I molecules is an essential mechanism involved in the maintenance of immune privilege and tolerance at the maternal-fetal interface [104].

An article by Ono and colleagues recently documented the potential role of donor MHC cross-dressing in tolerance of liver transplants in mice [97]. A large number of recipient DCs cross-dressed with donor MHC class I molecules was observed in mice undergoing spontaneous tolerance of liver allografts [97]. These cross-dressed DCs expressed high levels of T cell inhibitory programmed death ligand 1 (PD-L1) and high levels of IL-10 compared with non-cross-dressed DCs isolated from the graft [97]. In addition, the presence of these cross-dressed DCs was associated with high frequencies of programmed death protein 1 (PD-1)hi T cell immunoglobulin and mucin domain containing-3 (TIM-3)+ exhausted graft-infiltrating CD8+ T cells [97]. It is likely that, in this model, cross-dressed cells subverted the alloresponse by causing exhaustion and cell death of graft infiltrating CD8+ T cells thus inducing tolerance. Therefore, when recipient APCs expressing co-inhibitory receptors present donor MHC-peptide antigens, they are likely to promote T cell tolerance rather than rejection. Finally, a study by Mastoridis et al. investigated the presence of passenger leukocytes and recipient cells cross-dressed with donor MHC antigens in the blood of patients after liver and kidney transplantation [107]. In liver transplanted patients, very few donor leukocytes were detected while a substantial number of cross-dressed cells were found in all recipients [107]. Interestingly, antigen cross-dressing was mediated by donor-derived EVs enriched in PD-L1 being transferred along with donor HLA molecules to recipient cells [107]. Furthermore, DCs cross-dressed with these EVs in vitro expressed reduced levels of CD40 and CD86 costimulation molecules, produced less IL-6 and more IL-10 cytokines than DCs cross-dressed with EVs from healthy control individuals and inhibited the proliferation of CD8+ T cells [107]. In contrast, such “regulatory” EVs and cross-dressed cells were not observed in patients transplanted with an allogeneic kidney [107]. This study documented for the first time the preeminence of recipient cross-dressed cells over donor passenger leukocytes in clinical transplantation. These results are reminiscent of the observations made by Ono et al. in mouse liver transplantation and suggest that MHC cross-dressing of recipient APCs along with transfer of co-inhibitory molecules by EVs released by the allograft contributes to the immune privilege nature and tolerogenicity of liver transplants. Altogether, these studies suggest that intercellular transfer of MHC molecules may represent an essential element of T cell tolerance of alloantigens in pregnancy and transplantation.

Altogether, the aforementioned studies suggest that cross-dressing of recipient APCs with donor MHC molecules, acquired presumably from EVs released by the allograft can contribute to regulatory tolerance. This may occur through activation of CD4+Foxp3+ Tregs recognizing donor peptides bound to self-MHC class II molecules on recipient APCs (indirect presentation) and subsequent suppression of effector T cells recognizing intact donor MHC antigens on the same APCs (semi-direct presentation) [Fig. 3].Fig. 3 Model for suppression of alloreactive effector T cells by CD4+regulatory T cells (Tregs).This model postulates that CD4+ Tregs recognizing donor peptides bound to self-MHC class II molecules on recipient APCs (indirect pathway) can suppress effector CD4+ or CD8+ effector T cells recognizing intact donor MHC molecules displayed on the same recipient APCs through MHC cross-dressing (semi-direct pathway).

Fig. 3

5 Concluding remarks

MHC peptide complexes are regularly exchanged between leukocytes via cell-cell contact or extracellular vesicles. There is now ample evidence showing that this phenomenon plays an essential role in antigen recognition by T cells involved in the development and homeostasis of the immune system as well as protection against tumors and microbes. Recently, we and others have shown that allogeneic MHC class I and II molecules are regularly transferred from donor cells to recipient APCs after allotransplantation. MHC molecule transfer occurs via trogocytosis as well as extracellular vesicles, including exosomes, released by donor cells. Recipient APCs having acquired allogeneic MHC molecules can either present them in intact form on their membrane surface (semi-direct presentation) or in the form of peptides bound to self-MHC molecules (indirect presentation). Both semi-direct and indirect MHC antigen presentation leads to the activation of alloreactive T cells. Antigen presentation by recipient APCs cross-dressed with donor MHC molecules has now been documented after skin, bone marrow and solid organ transplantation in mice and patients and therefore represents a general phenomenon in transplantation. Since donor passenger leukocytes are scarce and rapidly eliminated by the host's immune system, it is likely that semi-direct rather than direct allorecognition is the driving force behind acute allograft rejection. In addition to its role in allograft rejection, some studies have documented the role of extracellular vesicles and donor MHC cross-dressing in fetal-maternal tolerance and liver allograft tolerance. This occurs via intercellular transfer of regulatory HLA-G MHC class I molecules as well as the presentation of donor MHC peptide complexes along with co-inhibitory molecules on recipient APCs. Further studies are needed to better understand the mechanisms by which intercellular exchange of MHC molecules influences transplant rejection and tolerance. Gaining insights into this phenomenon will lead to the development of novel immune therapies in clinical transplantation.

Funding

This study was supported by a grant from the National Institute of Health: NIH/NIDDK R01DK115618 .

Peer review under responsibility of Chang Gung University.
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